Hepatocyte growth factor, (HGF), is a protein expressed in the mesenchymal cells such as lung macrophages and fibroblasts, kupffer cells in the liver and leukocytes. HGF is a cytokine, which is secreted at cell damage and appears to have an importance for the regeneration of certain organs and for the healing of wounds. Chemically HGF is a glycoprotein, which first is synthesised as an inactive precursor. The precursor is cleaved to an active protein in the damaged organ via a particular activator. HGF binds to heparin, which seems to have importance for the activation of HGF and the binding to its receptor. The receptor binding HGF is c-MET. Since the c-MET-receptor only is down-regulated in damaged organ, it is only cells in these damaged organs that appear to respond on a HGF-receptor interaction.
HGF plays a important role in the cell-cell-interaction between mesenchyme cells and epithelium cells. Mesenchyme cells produces HGF which influences epithelial cells. The target cells of HGF are fully developed epithelial cells, wherein the most important cells are hepatocytes in the liver, epithelial cells in the proximal and distal tubuli in the kidney and type II epithelial cells in the lungs. HGF is regulated by TGF β (transfer growth factor β), which counteract the effects of HGF. HGF exhibits three effects on epithelial cells: mitogenic, motogenic and morphogenic effects. HGF acts both paracrine, ie., an effect on adjacent cells and endocrine, a long-distant effect, e.g. HGF is transported via blood from the lungs to for example the liver or the kidney.
HGF is formed and is present in high concentrations in the body at damage. Previous studies show a correlation between high serum concentrations of HGF and a good prognosis in pneumonia. The serum concentrations of HGF increase at acute infectious diseases. This has been registered via control of the concentrations of serum HGF in patients suffering from sepsis, pneumonia, infectious gastroenteritis, erysipelas, and urinary tract infections. The HGF values do not increase at chronic diseases, as well as at chronic hepatitis. This may be a reason for the formation of fibroses in such infections.
The effect of HGF has also previously been investigated on skin cells. The DNA synthesis is doubled in human skin fibroblasts after addition of more than 1.0 ng/ml of HGF to cultures media. The effect was inhibited using monoclonal antibodies against HGF.
The presence of chronic leg wounds in elderly patients and especially in the patients suffering from diabetes is a large problem in today's health care. These leg wounds depend on different causes such as inappropriate circulation and are therefore very difficult to heal. These patients usually suffer from venous insufficiency or combined venous and arterial insufficiency. At present, there is not any real satisfactory treatment. The methods available are time consuming, difficult and costly. The current methods include usage of a saline compress, enzymatic treatment using varidase to degrade fibrin, skin grafts and surgery of varix. These ulcers are nearly always contaminated by different bacterial flora. When the signs of infection are dominated the ulcers are treated by antibiotics according to the culture results. Though improvement of ulcer in general, the antibacterial treatment can seldom cure the ulcers.
During the course of pneumonia there are lots of patients, especially elderly, who do not recover in spite of successfully antibacterial treatment. This is the case in other serious lung injuries such as burn injuries that are complicated by infections.
Based on clinical studies the inventors mean that in such cases as mentioned before a combination of HGF local therapy and appropriate antibacterial treatment have synergetic effects that are considerably more than using either of the treatments alone.